CD74 (MHC class II invariant chain, Ii) is a non-polymorphic type II transmembrane glycoprotein. It is clear that, in addition to be an MHC class II chaperone, CD74 has a diversity of biological functions in physiological and pathological situations. CD74 also participates in other non-MHC II protein trafficking, such as angiotensin II type I receptor. In addition, CD74 is a cell membrane high-affinity receptor for macrophage migration inhibitory factor (MIF), D-dopachrome tautomerase (D-DT/MIF-2) and bacterial proteins. CD74 also regulates T-cell and B-cell developments, dendritic cell (DC) motility, macrophage inflammation, and thymic selection. The activation of receptor complex CD74/CD44 may lead to multiple intracellular signal pathways, such as the activation of the extracellular signal regulated kinase (ERK) 1 and 2, the PI3K-Akt signal transduction cascade, NFκB, and the AMP-activated protein kinase (AMPK) pathway. CD74 plays important roles in many inflammatory diseases, such as liver fibrosis, type I diabetes, systemic lupus erythematosus, and Alzheimer disease. In this study, we will focus on the immunological functions of CD74 molecules and its roles in immune-relevant disorders.

Studies clearly showed that CD52 can modulate T-cell activation either by its intracellular signal pathways or by the interaction of soluble CD52 and Siglec-10 expressing on T cells. However, the regulatory functions of CD52 on other immune cell subpopulations in organ transplantation require to be studied in the near future.

BackgroundLarge-size data on type-specific HPV prevalence in Southwest China are required to estimate the cervical cancer burden in the country and to prepare for HPV-based cervical screening program and further HPV vaccination of China. This HPV study is a pooled analysis of data from five years in Chongqing of China, which is cross-sectional in design using data collecting.ResultsThe positivity of HPV was 26.2% (10542/40311), single type was 25.7% (10360/40311), multiple type was 8.2% (3306/40311), high-risk HPV was 30.9% (12490/40311), and low-risk HPV was 2.9%(1169/40311). The most common genotypes were HPV16,52,58 and 18. HPV-positive women (n = 10542) were triaged by cytology, colposcopy or histological diagnosis. Among HPV-positive women, 43.8% had normal, 22.5% had ASCUS, 0.2% had LSIL, 12.6% had HSIL and 6.0% had ICC. The most common HPV genotypes were HPV16, 58 and 18 in ASCUS, HPV16, 18 and 58 in LSIL, HPV16, 58 and 33 in HSIL, and HPV16, 58 and 18 in ICC. The prevalence of Group 1/2A HPV types increased with increasing CIN grade and accounted for 96.05% of the CIN 3+ lesions, while HPV16 accounted for 71.1%. HPV-positive women steadily increased with age, peaking at 31–40 years.ConclusionThe type-specific prevalence rate of HPV 16 and HPV 18 were a little lower than the mean of international meta-analyses. Single HPV genotype infection was predominantly detected in different groups of cervical lesions in Chongqing, and HPV16, 52, 58 were the priority HPV types. The HPV genotyping study was found to be valuable for planning further preventive program for cervical cancer.

Monocytes and macrophages play a key role in defending pathogens, removing the dead cells or cell debris, and wound healing. The mammalian target of rapamycin (mTOR) inhibitor rapamycin (RPM) is widely used in clinics to treat patients with organ transplantation or tumors. The role of mTOR in monocyte/macrophage development remains to be clarified. Here we found that mTOR intrinsically controls monocyte/macrophage development, as evidenced by the decreased percentages and cell numbers of CD11bF4/80 cells resulting from mTOR inhibition in SCID mice, mTOR-deficient mice, and mixed chimera mice, and the in vitro colony formation and monocyte/macrophage induction assays. However, Lyzs-mTOR knockout mice displayed normal levels of monocytes/macrophages, indicating that mTOR is not essential for the survival and maturation of monocytes/macrophages. Further studies showed that mTOR deficiency significantly reduced macrophage colony-stimulating factor receptor CD115 expression at the transcriptional and translational levels. The molecular mechanism studies indicate that the impaired monocyte/macrophage development caused by mTOR deficiency is mainly a result of the overactivated STAT5 and subsequent downregulation of IRF8, but not the altered cell metabolism and autophagy. Therefore, our work identifies that mTOR is an intrinsic master for monocyte/macrophage development at the early stages through regulating STAT5-IRF8-dependent CD115-expressing pathway. Long-term usage of RPM may cause a defect of myeloid progenitors in bone marrow.

Thymic epithelial cells (TECs) are critical for the establishment and maintenance of appropriate microenvironment for the positive and negative selection of thymocytes and the induction of central immune tolerance. Yet, little about the molecular regulatory network on TEC development and function is understood. Here, we demonstrate that MTOR (mechanistic target of rapamycin [serine/threonine kinase]) is essential for proper development and functional maturation of TECs. Pharmacological inhibition of MTOR activity by rapamycin (RPM) causes severe thymic atrophy and reduction of TECs. TEC-specific deletion of Mtor causes the severe reduction of mTECs, the blockage of thymocyte differentiation and output, the reduced generation of thymic regulatory T (Treg) cells and the impaired expression of tissue-restricted antigens (TRAs) including Fabp2, Ins1, Tff3 and Chrna1 molecules. Importantly, specific deletion of Mtor in TECs causes autoimmune diseases characterized by enhanced tissue immune cell infiltration and the presence of autoreactive antibodies. Mechanistically, Mtor deletion causes overdegradation of CTNNB1/Beta-Catenin due to excessive autophagy and the attenuation of WNT (wingless-type MMTV integration site family) signaling in TECs. Selective inhibition of autophagy significantly rescued the poor mTEC development caused by Mtor deficiency. Altogether, MTOR is essential for TEC development and maturation by regulating proliferation and WNT signaling activity through autophagy. The present study also implies that long-term usage of RPM might increase the risk of autoimmunity by impairing TEC maturation and function.

Large cardiovascular outcome trials have reported favorable effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on heart failure. To study the potential mechanism of the SGLT2 inhibition in heart failure, we used the murine doxorubicin-induced cardiomyopathy model and identified the toll-like receptor 9 (TLR9), NAD-dependent deacetylase sirtuin-3 (SIRT3), and Beclin 1, acting in a complex together in response to empagliflozin treatment. The interactions and implications in mitochondrial function were evaluated with TLR9 deficient, SIRT3 deficient, Beclin 1 haplodeficient, and autophagy reporter mice and confirmed in a patient with SIRT3 point mutation and reduced enzymatic activity. The SGLT2 inhibitor, empagliflozin, protects the heart from doxorubicin cardiomyopathy in mice, by acting through a novel Beclin 1-toll-like receptor (TLR) 9-sirtuin-(SIRT) 3 axis. TLR9 and SIRT3 were both essential for the protective effects of empagliflozin. The dilated cardiomyopathy patient with SIRT3 point mutation and reduced enzymatic activity is associated with reduced TLR9 activation and the absence of mitochondrial responses in the heart after the SGLT2 inhibitor treatment. Our data indicate a dynamic communication between autophagy and Beclin 1-TLR9-SIRT3 complexes in the mitochondria in response to empagliflozin that may serve as a potential treatment strategy for heart failure.

These findings uncover a novel role of mTORC2 in Th9 cell differentiation and may have important implications for therapeutic intervention of allergic diseases.

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